By applying advances in molecular biology and molecular genetics to population based studies of HIV-1 infection, Viral Epidemiology Branch investigators help elucidate the distribution, determinants, and natural history of this cancer-associated virus. Chemokine Receptor Gene Polymorphisms Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous, and it is known that polymorphisms in chemokine receptor genes modulate the natural history. We recently demonstrated that polymorphisms in chemokine receptor genes may also explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy. We continued to lead the international meta-analysis of the effect of host genetics on the outcome of HIV infection. The meta-analysis seeks to increase statistical precision over that available from any single study. HIV RNA Levels The HIV RNA level is the strongest known predictor of prognosis among HIV-infected patients. We collaborated to demonstrate that a simple mathematical relationship exists between the HIV RNA level and survival time, such that a patient's cumulative exposure to viral replication predicts their survival. In developed areas, our studies of twins have enrolled sufficient numbers and follow-up will be complete by June 2003. Studies this year have demonstrated neither viral levels nor strain divergence in coinfected twins differed according to whether the twins were mono or dizygotic. Risk of infection was similar in both first and second born twins. Cesarean- delivered twins had a greatly reduced risk of infection. Because of changes in Kaposi's sarcoma and non-Hodgkin's sarcoma, cancer risk in the US population has been greatly affected by AIDS. However, the new antiretroviral therapies have abruptly changed the profile yet again, resulting in dramatic reductions of these cancers, almost to pre-AIDS levels. Notably, the incidence of types of NHL not related to AIDS has continued to increase throughout the 1990s. We also participated in a collaboration that demonstrated that the HIV RNA level and the CD4 cell count are the main predictors of mortality among HIV-infected African children, as is true in developed countries. Effect of Recent Thymic Emigrants on HIV-1 disease The concentration of T-cell receptor-rearrangement excision DNA circles (TREC) in peripheral-blood T cells is a marker of recent thymic emigrant T cells. We collaborated in a study of the predictive ability of measurements of TREC for clinical outcome in HIV-1-infected individuals. We found that the concentration of TREC in the peripheral T-cell pool complements HIV-1 RNA load and CD4 T-cell count in predicting the rate of HIV-1 disease progression. These data suggest that recent thymic emigrants have a role in the pathogenesis of HIV-1 disease.